Risk Of Atypical Femoral Fractures Research Articles

Latent metabolic bone disease, skeletal dysplasia and other conditions related to low bone formation among 38 patients with subtrochanteric femoral fractures: a retrospective observational study

SummarySubtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them.PurposeThe main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age.MethodsClinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022.ResultsAmong 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides.ConclusionIf clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF.

Current vision on mechanism of action of bisphosphonates. The effect of long-term administration of bisphosphonates on bone tissue (preclinical studies)

Osteoporosis (OP) is one of the common chronic diseases in the elderly, which requires long–term therapy. Bisphosphonates (BP) belong to the first-line choice medications for the treatment of OP, however, prolonged period of bisphosphonates use has been associated with increased risk of atypical femoral fractures (AFFs), medication-related osteonecrosis of the jaw (MRONJ) and the impact on fracture healing, which attracts increased attention to the current widespread use of them.The article presents the existing classes of BP according to their chemical structure and mechanism of action, differences in their antiresorptive potencies. The data of studies on animal models on the effect of BP on the mechanical properties of bone, fracture repair, as well as the development of MRONJ are presented.

High Frequencies of Genetic Variants in Patients with Atypical Femoral Fractures.

This study explores the genetic factors associated with atypical femoral fractures (AFF), rare fractures associated with prolonged anti-resorptive therapy. AFF are fragility fractures that typically appear in the subtrochanteric or diaphyseal regions of the femur. While some cases resemble fractures in rare genetic bone disorders, the exact cause remains unclear. This study investigates 457 genes related to skeletal homeostasis in 13 AFF patients by exome sequencing, comparing the results with osteoporotic patients (n = 27) and Iberian samples from the 1000 Genomes Project (n = 107). Only one AFF case carried a pathogenic variant in the gene set, specifically in the ALPL gene. The study then examined variant accumulation in the gene set, revealing significantly more variants in AFF patients than in osteoporotic patients without AFF (p = 3.7 × 10-5), particularly in ACAN, AKAP13, ARHGEF3, P4HB, PITX2, and SUCO genes, all of them related to osteogenesis. This suggests that variant accumulation in bone-related genes may contribute to AFF risk. The polygenic nature of AFF implies that a complex interplay of genetic factors determines the susceptibility to AFF, with ACAN, SUCO, AKAP13, ARHGEF3, PITX2, and P4HB as potential genetic risk factors. Larger studies are needed to confirm the utility of gene set analysis in identifying patients at high risk of AFF during anti-resorptive therapy.

Differences in bone histomorphometry between White postmenopausal women with and without atypical femoral fracture after long-term bisphosphonate therapy.

Bone histomorphometric endpoints in transilial biopsies may be associated with an increased risk of atypical femoral fracture (AFF) in patients with osteoporosis who take antiresorptives, including bisphosphonates (BPs). One way to test this hypothesis is to evaluate bone histomorphometric endpoints in age-, gender-, and treatment time-matched patients who either had AFF or did not have AFF. In this study, we performed transiliac bone biopsies in 52 White postmenopausal women with (n= 20) and without (n= 32) AFFs, all of whom had been treated for osteoporosis continuously with alendronate for 4-17yr. Despite the matched range of treatment duration (4-17yr), AFF patients received alendronate for significantly longer time (10.7yr) than non-AFF patients (8.0yr) (P= .014). Bone histomorphometric endpoints reflecting microstructure and turnover were assessed in cancellous, intracortical, and endocortical envelopes from transilial biopsy specimens obtained from BP-treated patients 3-6mo after AFF and from non-AFF patients with similar age-, gender-, and range of BP treatment duration. However, in both cancellous and intracortical envelopes, AFF patients had significantly lower wall thickness (W.Th) and higher osteoclast surface (Oc.S/BS) than non-AFF patients. In addition, AFF patients had significantly higher eroded surface (ES/BS) only in the intracortical envelope. None of the dynamic variables related to bone formation and turnover differed significantly between the groups. In conclusion, in the ilium of BP-treated patients with osteoporosis, AFF patients have lower thickness of superficial bone (lower W.Th) of the cancellous and cortical envelopes than non-AFF patients. AFF and non-AFF patients have a similar bone turnover rate in the ilium. Furthermore, in this population, as in previous work, AFF is more likely to occur in BP-treated patients with longer treatment duration.

Factors Affecting the Second Complete Atypical Femoral Fracture after the First Atypical Fracture

Objectives: Atypical femoral fracture (AFF) is an atypical low-energy subtrochanteric and diaphyseal femoral fracture. Even if bone fusion is achieved in patients with AFF, the risk of AFF in the contralateral femur must be considered. This study aimed to investigate the factors affecting complete AFF in the contralateral femur and conservatively treated incomplete AFF. Subject and Methods: Radiographs of 111 femurs in 104 AFF cases were examined, and the femurs were classified as follows: 85 contralateral femurs with complete AFF; 18 contralateral femurs with incomplete AFF; 8 femurs with incomplete AFF without surgical treatment. Various patients’ clinical data were collected, and we investigated the factors affecting the second complete AFF. Results: Complete fractures occurred in 10 (9.7%) of 103 femurs without incomplete AFF at the first visit and in 3 (37.5%) of 8 femurs with incomplete AFF. The Kaplan-Meier curve revealed that lateral cortical bone thickening and thigh pain were associated with significantly poorer prognoses (p = 0.026 and p = 0.013, respectively). Multivariate analyses revealed that eldecalcitol usage after AFF onset (p = 0.0094) and previous use of bisphosphonate or denosumab (p = 0.0126) were protective factors for second complete AFF and that the presence of thigh pain (p = 0.0134) was a risk factor for second complete AFF. Conclusions: Eldecalcitol administration after bone union of first AFF may prevent AFF recurrence. In addition, painful incomplete AFF has a high risk of developing a complete fracture.

Towards understanding how bisphosphonate-dependent alterations to nutrient canal integrity can contribute to risk for atypical femoral fractures: Biomechanical considerations and potential relationship to a real-world analogy.

Bisphosphonates are a class of drugs which have shown good efficacy in the treatment of post-menopausal osteoporosis, as well as a good safety profile. However, side-effects such as risk for atypical femoral fractures (AFF) have appeared, leading to a decline in use of the drugs by many patients who would benefit from the treatment. While patient characteristics have contributed to improved understanding of risk factors, the mechanisms involved that explain AFF risk have not appeared. Recently, the possibility that the mechanism(s) involved drug-induced modification of cells of the nutrient canals of the femur and subsequent compromise in the bone matrix has been published. The present Hypothesis article builds on the concept presented earlier and expands into biomechanical considerations. An analogy of the mechanisms involved to a real-life scenario is also presented. While this analogy has limitations, consideration of the biomechanical implications of progressive alterations to defects presented by compromised nutrient canal-bone matrix also presents potential relationships with AFF risk.

OA07 A case of severe osteoporosis treated with teriparatide following the development of bilateral atypical femoral fractures due to IV zoledronic acid

Abstract Introduction Atypical femoral fractures (AFF) are a rare complication of long-term anti-resorptive therapy. A literature review of 310 cases of AFF did reveal a median duration of bisphosphonate therapy of 7 years. Additionally, simultaneous glucocorticoid use was seen in 34% of the cases and was reported to have a 5-fold increase in one case series. Around 70% of patients do describe a prodrome of thigh pain and around quarter of all cases will have bilateral involvement. Case description A 59-year-old lady with a background diagnosis of Behçet’s disease was referred for continuation of osteoporosis care. History of Fractures 2003- left-sided distal radial fracture; 2017 - refractured again after a fall; left 5th metatarsal fracture a few months later. 2019 - right navicular fracture, left pubic rami fracture and left iliac wing fracture, after a fall from the bus In 2023, she has tripped and fell from the standing height resulting in a left femoral shaft fracture, which had radiological features of an atypical femoral fracture. She denied any prodromal thigh pain. The orthopaedic team did an intramedullary nailing to the left femoral shaft. X-ray of the right femur shaft revealed cortical thickening of right mid femoral shaft. Treatment History In 2009, she was started on oral bisphosphonate therapy and from 2020 to 2022 received 3 doses of IV zoledronic acid at the national Behçet’s centre in Birmingham. She has been on long-term steroid therapy due to the underlying Behçet's disease and was on prednisolone 7mg daily when she was referred to us. Management of AFF The orthopaedic team initially recommended a watch and wait policy for the right side; however, following discussions with the patient and with us, prophylactic nailing of the right femoral shaft was done 2 months later. Investigations DXA scan in 2022: spine T-score of−3.3 (L2 −3.6, L3 −3.9, L4 −3.7); femoral neck T-score of −2.5. Despite treatment with oral and then parenteral bisphosphonates for the last 12 years, there is a significant reduction in BMD with 18.2% decrease in the spine and 7.1% decrease in the femoral neck compared to the last DEXA in 2019. Management plan The next step was to treat her with teriparatide, which she is currently having without any problems. We shall continue it for 24 months. Discussion Atypical femoral fractures are rare. Anti-resorptive medication including bisphosphonates and denosumab are known to cause atypical femoral fractures. Teriparatide, being anabolic agent, is not associated with the increased risk of atypical femoral fractures. While there are no randomised controlled studies about the use of teriparatide in healing atypical femoral fractures, there are some case reports where teriparatide had shown improved fracture healing in AFF. After the 24 months, to ‘lock in the effects’ of teriparatide, an anti-resorptive medication will be required. Because both femoral shafts have received intramedullary nailing, we would consider IV zoledronic acid after the 24 months of teriparatide. This is the approach supported by the European Calcified Tissue Society in their systemic review and recommendations on ‘Medical Management of Patients After Atypical Femur Fractures’ (https://doi.org/10.1210/clinem/dgz295). Key learning points Consider atypical femoral fracture in patients who are on anti-resorptive therapy and complain of thigh/groin pain. Atypical femoral fractures can be bilateral; therefore, evaluate both sides. Teriparatide can be used to treat osteoporosis in patients with atypical femoral fracture, but considerations will have to be made in relation to subsequent therapy.

Surgical strategy of the treatment of atypical femoral fractures.

The atypical femoral fracture (AFF) has been attracting significant attention because of its increasing incidence; additionally, its treatment is challenging from biological and mechanical aspects. Although surgery is often required to manage complete AFFs, clear guidelines for the surgical treatment of AFFs are currently sparse. We reviewed and described the surgical treatment of AFFs and the surveillance of the contralateral femur. For complete AFFs, cephalomedullary intramedullary nailing spanning the entire length of the femur can be used. Various surgical techniques to overcome the femoral bowing common in AFFs include a lateral entry point, external rotation of the nail, and the use of a nail with a small radius of curvature, or a contralateral nail. In the case of a narrow medullary canal, severe femoral bowing, or pre-existing implants, plate fixation may be considered as an alternative. For incomplete AFFs, prophylactic fixation depends on several risk factors, such as a subtrochanteric location, presence of a radiolucent line, functional pain, and condition of the contralateral femur; the same surgical principles as those in complete AFFs can be applied. Finally, once AFF is diagnosed, clinicians should recognize the increased risk of contralateral AFFs, and close surveillance of the contralateral femur is recommended.

Are secondary effects of bisphosphonates on the vascular system of bone contributing to increased risk for atypical femoral fractures in osteoporosis?

Osteoporosis (OP) is a bone disease which affects a number of post-menopausal females and puts many at risk for fractures. A large number of patients are taking bisphosphonates (BPs) to treat their OP and a rare complication is the development of atypical femoral fractures (AFF). No real explanations for the mechanisms underlying the basis for development of where AFF develop while on BPs has emerged. The present hypothesis will discuss the possibility that part of the risk for an AFF is a secondary effect of BPs on a subset of vascular cells in a genetically at-risk population, leading to localized deregulation of the endothelial cell (EC)-bone cell-matrix units in nutrient channels/canals of the femur and increased risk for AFF. This concept of targeting ECs is consistent with location of AFF in the femur, the bilateral risk for occurrence of AFF, and the requirement for long term exposure to the drugs.

Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians.

The prevalence of osteoporosis is increasing in the United States. To evaluate low bone mass and osteoporosis treatments to prevent fractures. Ovid MEDLINE ALL, Ovid Evidence Based Medicine Reviews: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from 2014 through February 2022. Adults receiving eligible interventions for low bone mass or osteoporosis. Randomized controlled trials (RCTs) for fracture outcomes, and RCTs and large observational studies (n ≥1000) for harms. Abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE). We included 34 RCTs (in 100 publications) and 36 observational studies. Bisphosphonates and denosumab reduced hip, clinical and radiographic vertebral, and other clinical fractures in postmenopausal females with osteoporosis (moderate to high CoE). Bisphosphonates for 36 months or more may increase the risk for atypical femoral fractures (AFFs) and osteonecrosis of the jaw (ONJ), but the absolute risks were low. Abaloparatide and teriparatide reduced clinical and radiographic vertebral fractures but increased the risk for withdrawals due to adverse events (WAEs; moderate to high CoE). Raloxifene and bazedoxifene for 36 months or more reduced radiographic vertebral but not clinical fractures (low to moderate CoE). Abaloparatide, teriparatide, and sequential romosozumab, then alendronate, may be more effective than bisphosphonates in reducing clinical fractures for 17 to 24 months in older postmenopausal females at very high fracture risk (low to moderate CoE). Bisphosphonates may reduce clinical fractures in older females with low bone mass (low CoE) and radiographic vertebral fractures in males with osteoporosis (low to moderate CoE). Few studies examined participants with low bone mass, males, or Black-identifying persons, sequential therapy, or treatment beyond 3 years. Bisphosphonates, denosumab, abaloparatide, teriparatide, and romosozumab, followed by alendronate, reduce clinical fractures in postmenopausal females with osteoporosis. Abaloparatide and teriparatide increased WAEs; longer duration bisphosphonate use may increase AFF and ONJ risk though these events were rare. American College of Physicians. (PROSPERO: CRD42021236220).

Effects of bisphosphonates on appendicular fracture repair in rodents.

The balance between osteoclastic bone resorption and osteoblastic bone formation is ultimately responsible for maintaining a structural and functional skeleton. Despite their strength, bones do break and the main cause of fractures are trauma and decreased bone mineral density as a result of aging and/or pathology that weakens the bone's microarchitecture and subsequently, its material properties. Osteoporosis is a disease marked by increased osteoclast activity and decreased osteoblastic activity tipping the remodeling balance in favor of bone resorption and can be caused by aging, glucocorticoids, disuse and estrogen-deficiency. Ultimately, this leads to brittle and weaker bones which become more prone to trauma or stress-induced fractures. The current treatment for preventing and treating osteoporotic fractures is the use of antiresorptive drugs such as bisphosphonates (BPs) and denosumab, but unfortunately, their long-term use, especially with alendronate and ibandronate, has been associated with increased risk of atypical femoral fractures (AFFs); femoral diaphyseal fractures distal to the lesser trochanter but proximal to the supracondylar flare. The purpose of this review is to examine the information that exists in the literature examining the effects of BPs on fracture repair of long bones in rodent (rat and mouse) models. The focus on rodents stems from the scientific community's unresolved need to develop small animal models to examine the molecular, cellular, tissue and biomechanical mechanisms responsible for the development of AFFs and how best they can be treated.

RF30 | PSAT138 Romosozumab-aqqg in the Treatment of Osteoporosis in a Patient with Hypophosphatasia

Abstract Background Hypophosphatasia (HPP) is a rare inherited condition that causes osteomalacia and recurrent fractures. Therapeutic options for osteoporosis in patients with concomitant HPP are limited due to concerns for a greater likelihood of atypical femoral fractures (AFF) with anti-resorptive agents such as bisphosphonates and denosumab. We present a patient with HPP and OP who was treated with the anti-sclerostin antibody romosozumab-aqqg (Romo). Clinical Case An 81-year-old female was referred for management of OP. Fracture history included a hip fracture around age 40, and bilateral metatarsal fractures around age 65. Her initial DXA scan at age 57 showed osteoporosis at the lumbar spine (LS, T-score: -2.8) and femoral neck (FN, T-score -3.2). Sequential osteoporosis treatment over the subsequent 20 years included several years of oral bisphosphonates, hormone replacement therapy, teriparatide for one year followed by two years of alendronate, and one denosumab injection. Despite almost 20 years of pharmacologic osteoporosis treatment, her bone mineral density (BMD) worsened. HPP was suspected on the basis of low serum alkaline phosphatase (AP) levels ranging from 25-37 U/L (ref: 35-104 U/L). The diagnosis was substantiated by an elevated plasma vitamin B6 level of 305 mcg/L (ref: 5-50 mcg/L) and confirmed by genetic testing showing a diagnostic missense mutation c.571G>A in exon 6 in the ALPL gene. After diagnosing HPP, her osteoporosis was treated with an additional year of teriparatide followed by raloxifene, which she tolerated poorly. Following two years of expectant management, during which time her BMD worsened despite calcium and vitamin D supplementation to T-scores of –4.4 at the LS, she was started on Romo. After 11 monthly injections, a follow up DXA scan showed improvements of 21%, and 10% at the LS and total hip, respectively. These changes were substantially greater than what she experienced with her first year of teriparatide therapy (+4% and +8%, respectively). Blood AP remained low on Romo (37 IU/L and 29 IU/L at 9 and 12 months post-Romo initiation). She tolerated Romo and well and experienced no fractures during treatment. Discussion Management of osteoporosis in patients with HPP is challenging, as bisphosphonates and denosumab are generally avoided due to concern for an increased risk of AFF. Case reports of patients with HPP have suggested good BMD response to teriparatide. To our knowledge, this is the first report of a patient with HPP and osteoporosis treated with Romo. In our patient, Romo did not significantly impact serum AP, but improved BMD significantly more than in response to teriparatide. In conclusion, Romo is a potential treatment option for OP in patients with HPP for whom limited alternatives exist. Optimal osteoporosis treatment following a 1-year course of Romo remains to be determined. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 1:05 p.m. - 1:11 p.m.

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: Osteoporosis management.

Fractures occur in about half of older White women, and almost a third of older White men. However, 80% of the older individuals who have fractures do not meet the bone density definition of osteoporosis, suggesting that this definition is not an appropriate threshold for offering treatment. Fracture risk can be estimated based on clinical risk factors with or without bone density. A combination of calculated risk, fracture history, and bone density is used in treatment decisions. Medications available for reducing fracture risk act either to inhibit bone resorption or to promote bone formation. Romosozumab is unique in that it has both activities. Bisphosphonates are the most widely used interventions because of their efficacy, safety, and low cost. Continuous use of oral bisphosphonates for >5 years increases the risk of atypical femoral fractures, so is usually punctuated with drug holidays of 6-24 months. Denosumab is a further potent anti-resorptive agent given as 6-monthly s.c. injections. It is comparable to the bisphosphonates in efficacy and safety but has a rapid offset of effect after discontinuation so must be followed by an alternative drug, usually a bisphosphonate. Teriparatide stimulates both bone formation and resorption, substantially increases spine density, and reduces vertebral and non-vertebral fracture rates, though data for hip fractures are scant. Treatment is usually limited to 18-24 months, followed by the transition to an anti-resorptive. Romosozumab is given as monthly s.c. injections for 1 year, followed by an anti-resorptive. This sequence prevents more fractures than anti-resorptive therapy alone. Because of cost, anabolic drugs are usually reserved for those at very high fracture risk. 25-hydroxyvitamin D levels should be maintained above 30 nmol/L, using supplements if sunlight exposure is limited. Calcium intake has little effect on bone density and fracture risk but should be maintained above 500 mg/day using dietary sources.

Bisphosphonate Drug Holidays: Evidence From Clinical Trials and Real-World Studies.

ABSTRACTBisphosphonates (BPs) are commonly used in the treatment of osteoporosis and are effective in the prevention of fragility fracture. Long‐term use has been associated with the development of atypical femur fractures (AFFs) and osteonecrosis of the jaw (ONJ). Drug holidays seek to reduce the risk of insufficiency fractures (AFFs) while maintaining durable effects of long‐term treatment in the prevention of fragility fracture. Guidelines suggest that BP drug holidays be considered after 3 to 5 years. However individual factors impacting this decision and outcomes are unclear. This review examines key factors in the planning of a safe BP drug holiday and surrogate markers of fracture risk in patients discontinuing treatment. Fifteen randomized control trials and 19 real‐world studies were included, including nationwide prospective studies from several countries. Increases in bone turnover markers (BTMs) and reductions in bone mineral density (BMD) were generally observed during BP drug holidays. Resurgent bone turnover was problematic in high‐risk patients in whom fractures recurred as early as 12 months following a drug holiday. Risk factors for holiday‐related fractures included older age, low hip BMD, underweight, low medication adherence, and prevalent/incident fractures. Zoledronic acid conferred the most durable reduction in fractures, particularly after six annual infusions. Five years of alendronate was insufficient in preventing vertebral fractures in high‐risk patients embarking on a drug holiday. Relatively faster offset of antiresorptive effect was seen in risedronate users with more frequent fractures than alendronate during a drug holiday. Studies directly counterbalancing effects of long‐term treatment on AFF risk versus drug holiday outcomes in the same population were lacking. In the absence of persistently high fracture risk and following a specific treatment duration dependent on the BP used, drug holidays are safe and mitigate the risk of AFF. However, anti‐resorptive effects diminish over time; ongoing monitoring and careful planning of BP resumption is necessary. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Bisphosphonates in Total Joint Arthroplasty: A Review of Their Use and Complications.

BackgroundConsiderable interest has been expressed in the use of bisphosphonates to treat periprosthetic osteoporosis with the clinical goals of reducing periprosthetic fractures and prolonging implant survival.MethodsA systematic review was performed with the goal of identifying both basic science and clinical studies related to the risks and benefits of bisphosphonate use in total joint arthroplasty.ResultsStudies have shown that bisphosphonates may increase early bony ingrowth, decrease the postoperative loss of bone mineral density, and increase the longevity of implants by reducing the need for revisions secondary to aseptic loosening. Continuing bisphosphonates for 1 year postoperatively seems to provide the greatest benefit, with only marginal benefit being shown by continuing therapy for up to 2 years. Current data present some concerns for an increased risk of periprosthetic fractures especially in younger patients, and prolonged therapy is not recommended due to the potential risk of atypical femur fractures. Patients should be counseled regarding the risk of side effects of bisphosphonates, including the risk of osteonecrosis of the jaw, which is a rare but serious side effect. They should also be counseled on the risk of atypical femur fractures and gastrointestinal intolerance.ConclusionsOrthopedic surgeons could consider bisphosphonates for up to 1 year postoperatively regardless of the patient’s prior bone mineral density, after discussion regarding the risks and benefits with the patient.

Biomechanical analysis of the correlation between mid-shaft atypical femoral fracture (AFF) and axial varus deformation

BackgroundAtypical femoral fractures (AFF) are diaphyseal fractures of the elderly that occur at the end of a minor trauma. The objective of this biomechanical study, using finite element modelling, was to evaluate the variations of the femoral diaphysis fracture indicator according to the variations of the mechanical axis of the lower limb, which can explain all the different atypical fracture types identified in the literature.MethodsIn order to measure variations in stress and risk factors for fracture of the femoral diaphysis, the distal end of the femur was constrained in all degrees of freedom. An axial compression load was applied to the femoral head to digitally simulate the bipodal support configuration in neutral position as well as in different axial positions in varus/valgus (− 10°/10°).ResultsThe maximum stress value of Von Mises was twice as high (17.96 ± 4.87 MPa) at a varus angle of − 10° as in the neutral position. The fracture risk indicator of the femoral diaphysis varies proportionally with the absolute value of the steering angle. However, the largest simulated varus deformation (− 10°) found a higher risk of diaphysis fracture indicator than in valgus (10°).ConclusionsVariations in the mechanical axis of the lower limb influence the stress distribution at the femur diaphysis and consequently increase the risk of AFF. The axial deformation in varus is particularly at risk of AFF. The combination of axial deformation stresses and bone fragility consequently contribute to the creation of an environment favorable to the development of AFF.Trial registration: ‘retrospectively registered’.

Bisphosphonates and the risk of atypical femur fractures.

Bisphosphonates are effective in reducing hip and other fractures. However, concerns about atypical femur fractures (AFFs) have contributed to substantially decreased bisphosphonate use, and hip fracture rates may be increasing. Despite this impact, important uncertainties remain regarding AFF risks including the association between bisphosphonate use and other risk factors such as BMD, age, weight, and race. To address this evidence gap, a cohort study of 196,129 women ≥50years of age in the Southern California Kaiser Permanente HMO women (with ≥1 bisphosphonate prescription) were studied; the primary outcome was radiographically-adjudicated AFF between 2007 and 2017. Risk factors including bisphosphonate use and race were obtained from electronic health records. Multivariable Cox models were used for analysis. Benefit-risk was modeled for 1-10years of bisphosphonates to compare fractures prevented vs. AFFs associated. Among 196,129 women, 277 (0.1%) sustained AFFs. After multivariable adjustment, AFF risk increased with longer bisphosphonate duration: hazard ratio (HR) increased from HR=8.9 (95%CI: 2.8,28) for 3-5years to HR=43.5 (13.7138.1) for >8years. Hip BMD, surprisingly, was not associated with AFF risk. Other risk factors included Asian ancestry (HR=4.8 (3.6, 6.6)), short stature, overweight, and glucocorticoid use. Bisphosphonate discontinuation was associated with rapid decrease in AFF risk. Decreases in osteoporotic and hip fractures risk during 1-10years of bisphosphonates far outweighed the increase AFF risk in Caucasians, but less so in Asians. In Caucasians, after 3years 149 hip fractures were prevented with 2 AFFs associated compared to 91 and 8 in Asians. The evidence for several potential mechanisms is summarized with femoral geometry being the most likely to explain AFF risk differences between Asians and Caucasians. The results from this new study add to the evidence base for AFF risk factors and will help inform clinical decision-making for individual patients about initiation and duration of bisphosphonate therapy and drug holidays.

Long-term safety of eldecalcitol in Japanese patients with osteoporosis: a retrospective, large-scale database study

This real-world study evaluated whether long-term use of eldecalcitol (ELD) increases the risk of adverse events (AEs), namely, hypercalcemia, acute kidney injury (AKI), and urolithiasis, and analyzed the ELD-induced risk of rare AEs such as osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF). Patient records were retrieved from Medical Data Vision (MDV) and Japan Medical Data Center (JMDC) databases. The ELD-treated osteoporosis patient cohort (ELD cohort) was analyzed to determine the incidence rate of the aforementioned AEs. The patient cohort that was prescribed active vitamin D3 other than ELD (AVD cohort) was analyzed as the reference. Incidence rates of hypercalcemia, AKI, and urolithiasis in the ELD cohort were 0.942, 0.517, 2.465 events per 100 person-years, respectively, in the MDV dataset, and 0.687, 0.155, 3.785, respectively, in the JMDC dataset. The incidence rates of these AEs in the ELD cohort remained relatively constant throughout ELD treatment. A small number of patients experienced ONJ or AFF during ELD or AVD treatment. The number of ONJ and AFF cases in the both cohorts decreased over time. The two cohorts showed no difference in the concomitant use of anti-bone resorptive agents such as bisphosphonates and denosumab. The risk of hypercalcemia and AKI associated with ELD use observed in this retrospective analysis is similar to that reported previously in the Japanese post-marketing surveillance of ELD. Furthermore, ELD, similar to AVD, may not increase the risk of ONJ and AFF.

Indications for initiation of drug therapy and modern therapy protocols in patients with osteoporosis

Introduction. Pharmacotherapy and physical therapy in patients with osteoporosis are aimed at increasing bone density and reducing the risk of fall in order to prevent fractures. Medications approved for the treatment of osteoporosis reduce the risk of fracture, either by reducing bone resorption or by stimulating bone formation. Bisphosphonates are most widely used antiresorptive agents that lower bone turnover markers to premenopausal levels and reduce fracture rates. Bisphosphonates bind to bone minerals and have a long-lasting effect. Long-term, continuous use of oral bisphosphonates is usually interspersed with drug breaks of 1-2 years to reduce the risk of atypical femoral fractures. Denosumab is a monoclonal antibody that also acts as an antiresorptive and it targets receptor activators of nuclear factor-?B ligand thus inhibiting the formation and function of osteoclasts. Denosumab is administered as a subcutaneous injection every 6 months. Anti-fracture effects of denosumab are similar to those of bisphosphonates, but there is a marked loss of antiresorptive effect 7 months after the last dose, which may lead to recurrent vertebral fractures. Anabolic drugs work by stimulating bone formation. Teriparatide and abaloparatide bind to the parathyroid hormone-1 receptor and are given as daily subcutaneous injection for up to 2 years. Romosozumab is a monoclonal antibody that targets sclerostin, stimulates bone formation and inhibits resorption. The effects of anabolics are transient, so it is necessary to switch to antiresorptive medications. Conclusion. It is a matter of great importance to determine the optimal strategy for cycles of anabolics, antiresorptive drugs and therapy-free periods.

ALPL Genotypes in Patients With Atypical Femur Fractures or Other Biochemical and Clinical Signs of Hypophosphatasia.

Hypophosphatasia (HPP) is a rare metabolic disorder caused by deficiency of alkaline phosphatase (ALP) enzyme activity, leading to defective mineralization, due to pathogenic variants of the ALPL gene, encoding the tissue nonspecific alkaline phosphatase (TNSALP) enzyme. Inheritance can be autosomal recessive or autosomal dominant. An abnormal ALPL genetic test enables accurate diagnosis, avoiding the administration of contraindicated antiresorptive drugs that, in patients with HPP, substantially increase the risk of atypical femur fractures (AFFs) and worsen the fracture healing process that is usually already compromised in these patients. Performing ALPL genetic testing to identify rare variants in suspected adult patients with HPP. Comparing frequencies of ALPL common variants in individuals with biochemical and/or clinical signs suggestive of adult HPP and non-HPP controls, and among different clinical subgroups of patients with a clinical suspicion of adult HPP. Patients with suspected adult HPP were retrospectively selected for the genetic testing of the ALPL gene. Patients included were from 3 main European Bone Units (Florence, Naples, and Geneva); 106 patients with biochemical and/or clinical signs suggestive of a mild form of HPP were included. Genetic testing led to the identification of a heterozygote rare variant in 2.8% of cases who were initially referred as suspected osteoporosis. The analysis of frequencies of ALPL common variants showed a high prevalence (30.8%) of homozygosity in subjects who developed an AFF, in association with normal serum total ALP activity. The results suggest homozygosity of common ALPL variants as a possible genetic mark of risk for these fractures.